Kelly Dougherty, Ph.D., is an Assistant Professor of Pediatrics at University of Pennsylvania (UPenn) Perelman School of Medicine and The Children's Hospital of Philadelphia (CHOP). Dr. Dougherty proposes a comprehensive, interdisciplinary training program that will provide her with the skills and experience necessary to develop into an independent academic patient-oriented investigator in pediatric research, focusing on clinical trials addressing nutrition- and physical activity-related issues affecting children with sickle cell disease (SCD). Her career development will be guided by an accomplished team of investigators in nutrition, growth, chronic disease, stable isotope assessment, ophthalmology, epidemiology / study design and biostatistics. Her primary mentor, Virginia Stallings, M.D. has conducted pediatric clinical nutrition and chronic disease research for the last 27 years and as Director of the Office of Faculty Development at CHOP, has an superb reputation for supporting the development of junior faculty into independent, NIH-funded, clinical investigators. The proposed mentored experience will take place in one of the most outstanding nutrition and SCD clinical research environments in the country. Dr. Dougherty's training will include advanced formal coursework in research design, biostatistics, research ethics and stable isotopes. This training is crucial to build upon the foundations of nutrition and SCD research knowledge that she obtained during her postdoctoral fellowship and UPenn Masters in Translational Research (MTR) thesis work and to prepare her for future R01 submissions to conduct nutrition intervention studies in children with SCD. The proposed research project will focus on suboptimal vitamin A (vit A) status which is prevalent in children with type SS sickle cell disease (SCD-SS) and associated with hospitalizations and poor growth and hematological status. The preliminary data in children with SCD-SS show that vit A supplementation at the dose recommended for healthy children failed to improve vit A status, resulting in no change in hospitalizations, growth or dark adaptation. This indicates an increased vit A requirement most likely due to chronic inflammation, low vit A intake and possible stool or urine loss. The dose of vit A needed to optimize vit A status in subjects with SCD-SS is unknown. The proposed research study will establish the safety and efficacy of vit A supplementation doses (3000 and 5000 IU/d) compared to placebo over 3 months in 66 children with SCD-SS, age 9-to 18-yrs and test the impact of vit A supplementation on the key functional and clinical outcomes. The key safety measures are concurrently elevated serum retinol (age specific) and liver function tests (3x age specific). Efficacy is evaluated by repletion of liver vt A stores using state of the art stable isotope methods. In SCD-SS, total body vit A pool size and liver vit A concentration are assessed before and after the 3 month intervention using the deuterated-retinol-dilution technique. Baseline vit A status will be assessed in similar healthy subjects as a comparison group. Vit A therapy has great promise to safely and economically improve complications and quality of life for patients with SCD. Well-designed trials are urgently needed to determine the clinical impact of vit A supplementation and this study is the next step.